Therapeutic effects of retromer stabilization in Amyotrophic Lateral Sclerosis

Protein aggregation and misfolding likely contribute to motor neuron (MN) cell death in Amyotrophic Lateral Sclerosis (ALS). Their clearance may represent a therapeutic strategy with the potential to enter the clinical practice. Unlike proliferating cells, neurons degrade toxic products through the ubiquitin-proteasome system, or the autophagy-lysosomal pathway. Unfortunately, defects of the autophagy flux and of the lysosomal compartment are common traits of ALS. Delivery of proteolytic enzymes to the lysosome compartment needs the coordinated action of multiple protein regulators, including a highly conserved multi-proteins assembly named retromer. We found that VPS35/VPS26, i.e. two core members of the retromer protein assembly, are substantially down-regulated in MNs of ALS (G93A) mice. Impairment of the retromer functionality occurs early in G93A mice, anticipating the clinical onset of the disease. The retromer complex has been the object of pharmacological studies, proving that it is possible to increase its stabilization improving its functionality. We successfully synthetized a small array of molecular chaperones, selecting an early lead that efficiently increases retromer stabilization and functionality in G93A mice, leading to a substantial amelioration of clinical outcomes and MNs cell survival. Here we propose to clarify the molecular mechanism of action of our chaperones by biophysical and structural studies on the target (X-ray, Cryo-EM, NMR, microscale thermophoresis).

Members:
Eloise Mastrangelo (Principal investigator)
Mario Milani